Overexpression of coupling factor 6 attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice.

Abstract

BACKGROUND:

Regular exercise improves systolic cardiac dysfunction through Akt cascade-mediated physiological hypertrophy in congestive heart failure. Tissue acidosis impairs Akt cascade, and coupling factor 6 induces tissue acidosis via activation of ecto-F(1)F(o) complex. We tested the hypothesis that coupling factor 6 attenuates physiological cardiac hypertrophy induced by exercise and its benefit in mice.

METHODS AND RESULTS:

Adult wild-type mice (n = 20) and coupling factor 6-overexpressing transgenic mice (n = 20) were divided into two groups with or without 4-week exercise consisting of 90-min swimming twice daily. Left ventricular posterior wall and interventricular septum thicknesses were increased by 0.12 ± 0.1 and 0.16 ± 0.1 mm, respectively, after 4-week swimming in wild-type mice (both P < 0.01), but unchanged in transgenic mice. Fractional shortening was increased from 37 ± 1 to 41 ± 1% after 4-week swimming in wild-type mice (P < 0.05), whereas it was unchanged in transgenic. The insulin-like growth factor 1 (IGF-1) receptor protein and its phosphorylated form in the heart were both increased by 1.83 ± 0.23 and 1.83 ± 0.09 times, respectively, after 4-week swimming in wild-type mice (both P < 0.05), but were unchanged in transgenic. Downstream phosphoinsulin receptor substrate 1, phosphoinositide 3-kinase, and phospho-Akt were increased by 2.22 ± 0.22, 1.78 ± 0.31, and 2.24 ± 0.49 times, respectively, in wild-type mice (all P < 0.05), but were unchanged in transgenic. Restoration of phospho-Akt by IGF-1 injection recovered left ventricular hypertrophy and systolic function after 4-week swimming in transgenic.

CONCLUSION:

Overexpression of coupling factor 6 attenuates exercise-induced physiological cardiac hypertrophy by downregulating Akt signaling, thereby cancelling its benefit for cardiac function in mice. Reduction in coupling factor 6 level seems to be useful for drawing the exercising effects on cardiac function.

• Authors: Shigeki Sagara, Tomohiro Osanai, Taihei Itoh, Kei Izumiyama, Shuji Shibutani, Kenji Hanada, Hiroaki Yokoyama, Yuko Yamamoto, Takashi Yokota, Hirofumi Tomita, Koji Magota, Ken Okumura
• Journal: Journal of hypertension (J Hypertens) Vol. 30 Issue 4 Pg. 778-86 (Apr 2012) ISSN: 1473-5598 [Electronic] England
• PMID: 22306848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oxidative Phosphorylation Coupling Factors
• Phosphoproteins
• RNA, Messenger
• Insulin-Like Growth Factor I
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• F(6) ATPase
• Mitochondrial Proton-Translocating ATPases

Topics

• Adaptation, Physiological
• Animals
• Blood Pressure (drug effects, physiology)
• Disease Models, Animal
• Gene Expression
• Heart Ventricles (drug effects, pathology)
• Hypertrophy, Left Ventricular (etiology, genetics, metabolism)
• Insulin-Like Growth Factor I (genetics, metabolism, pharmacology)
• Mice
• Mice, Transgenic
• Mitochondrial Proton-Translocating ATPases (genetics, metabolism)
• Oxidative Phosphorylation Coupling Factors (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoproteins
• Physical Exertion
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction
• Swimming
• Ventricular Septum (drug effects, pathology)